Bile salt transport is an essential hepatic function in both normal physiology and in pathophysiologic diseases of the liver, biliary tract, and cardiovascular system. The rate-limiting step in bile salt transport is canalicular secretion, which is mediated by the bile salt transporter, Abcb11. We have developed transgenic mice (TTR-Abcb11) that functionally over-express Abcbl 1 in the liver. These mice hypersecrete biliary lipids and have altered expression of several hepatic lipid and metabolic genes. However, the roles of Abcbl 1 in pathophysiologic states, and the mechanisms responsible for this phenotype, remain poorly understood. The purpose of the proposed studies is to determine the role of Abcbl 1 in cholelithiasis (Specific Aim 1a) and hepatic steatosis (Specific Aim 1b), and characterize the hepatic cell signaling mechanisms responsible for these phenotypic alterations observed in the TTR-Abcb11 mice (Specific Aim 2). Cholelithiasis is a major health problem affecting over 20 million Americans annually. A family history of gallstones has been identified as a strong risk factor for the development of gallstones, suggesting a genetic basis to cholelithiasis, however, specific gallstone susceptibility genes have not yet been discovered. A major "gallstone locus" termed Lith 1 has been identified on mouse chromosome 2, which co- localizes to the chromosomal mapping position of Abcbl 1. We have recently shown that Abcbl 1 overexpression increases the rate of gallstone formation in mice fed a lithogenic diet. We will prove that Abcbl 1 is a "gallstone gene," which not only increases the rate of gallstone formation but truly confers increased susceptibility to gallstone disease. Obesity and the metabolic syndrome are an epidemic in the United States. Non-alcoholic fatty liver disease (NAFLD), which is associated with the metabolic syndrome, now represents the most common cause of abnormal liver function tests. "Thrifty genes" are genes that may have conferred a survival advantage to humans thousands of years ago, yet may be a cause of obesity, fatty liver, and other diseases associated with the metabolic syndrome on current American high fat diets. We have hypothesized that Abcbl 1 is a "thrifty gene," and we will explore the role of Abcbl 1 in the development of hepatic steatosis. The role of bile salts in gene regulation and hepatic cell signaling is an emerging area of research. Bile salts are now known to serve as ligands for nuclear receptors, including FXR. We will characterize the role of bile salts in regulating gene and protein expression in the TTR-Abcb11 model as a means to establish the mechanism by which Abcbl 1 predisposes to cholelithiasis and hepatic steatosis.